Synthetic polymeric biomedical materials are widely used in medicine and surgery for many applications, including implantation devices, such as heart valves, vascular grafts, tendons, reinforcing meshes, esophageal prostheses, ureter and gastrointestinal segments, drug-delivery implants, and the like, as well as for complex devices that simulate physiological processes, such as artificial kidney/blood dialysis, artificial lung/blood oxygenation, artificial hearts, artificial pancreas systems, and the like. In many of these applications, the synthetic polymeric materials are in direct contact with blood. Therefore, there has been considerable activity in developing methods for making these materials hemocompatible and preventing or reducing the risk of foreign surface-induced thrombosis.
One approach to solving this problem has been to chemically modify the polymer with one or more compounds that inhibit the blood clotting process. Polymers modified with pyrolytic carbon, hydrophilic monomers and other surface active compounds have been used to inhibit the initial stages of thrombus formation, i.e. adsorption of plasma proteins, including the coagulation proteins, to the polymer surface, followed by activation of contact factors, platelet (thrombocyte) adhesion, aggregation and activation. Modification of polymers with fibrinolytic enzymes, such as urokinase, fibrinolysin (plasmin) and streptokinase has also been reported to inhibit clot (thrombus) formation at the later stages of the coagulation process, i.e. a cascading system in which inactive precursor proteins are activated by the active form of the preceding protein in the cascade, culminating in the formation of a fibrin clot by the thrombin-mediated aggregation of fibrinogen molecules. However, fibrinolytic enzymes are useful for only a short-term increase in hemocompatibility because, when introduced into a living organism, they quickly lose activity due to the action of inhibitors and other denaturing agents in the blood. The natural anticoagulant, heparin has been widely studied as polymer surface modifier for longer term hemocompatibility, because of its physiological stability and high anticoagulant activity, although the presence of heparin on a polymer surface has been reported to increase the adherence of platelets. The mechanism of the anti-coagulant activity of heparin is not well understood.
Several approaches have been used for attaching heparin and other biologically active compounds to polymer surfaces to enhance their hemocompatibility. One method employs modification of a surface, such as an artificial blood vessel, with a polymeric gel incorporating an active compound. For example, heparin can be mechanically incorporated into the structure of a polyvinyl alcohol gel, followed by cross-linking of the heparin molecules using a mixture of glutaraldehyde and formaldehyde. However, the biological activity of the heparin is significantly decreased due to self-crosslinking, with resulting inaccessibility of active sites to blood stream substrates. Ionic immobilization of heparin on polymeric materials, such as by complexing with a quaternary ammonium compound, e.g. tridodecylmethylammonium chloride or benzalkonium chloride, has also been reported. However, the relative weakness of ionic bonds results in leaching of heparin into the blood stream over a period of time, with subsequent loss of activity at the implant surface. Covalent bonding of heparin to polymeric gels and polymer surfaces has also been reported. For example, poly(oxyethyl acrylate) or agarose gels may be activated with cyanogen bromide, followed by reaction of the activated gel with heparin. However, not only is cyanogen bromide toxic, but the activity of the heparin is decreased and only a small amount of heparin is bindable by this method. Other methods of covalently binding heparin to polymer surfaces include the forming of heparin derivatives, such as the acid hydrazide of heparin, silylated heparin, ethyleneimine-heparin, carbodiimide-heparin, a cyanuric chloride heparin adduct, and the like, prior to reaction with the polymer surface. However, again, the activity of the heparin is greatly decreased.
Other reported methods employ radiation-induced graft copolymerization of polymeric materials with biologically active compounds. For example, an unsaturated derivative of the fibrinolytic enzyme, plasmin, was bound to a polymer in this manner. However, at the gamma radiation dose employed, the enzymatic activity of the plasmin was markedly decreased. A similar reduction in enzymatic activity was reported in a method of radiation-induced graft copolymerization with the acid chloride of acrylic or methacrylic acid, followed by treatment of the graft copolymer with an aqueous solution of a serine protease. Heparin, graft copolymerized in this manner, produced a high degree of thrombocyte adhesion when in contact with the blood stream.
In view of the foregoing, there is still a need for biologically compatible, polymers for use as medical devices. In particular, there is a need for polymeric materials that are chemically modified with one or more compounds that inhibit the blood clotting process or compounds that perform other pharmacologic functions. More particularly there is a need for polymeric materials that are chemically modified with biologically active compounds that retain a high level of activity when incorporated into the polymeric material and that exhibit the activity over a long term period of weeks, months or years.